Antagonists in general possess the property of reversing a previously administered drug (the agonist). For example, the antagonist naloxone is well known for use in reversing selected properties of narcotic agonists. Antagonists of narcotics are believed to function by binding competitively to opioid receptors, thereby preventing occupation of the agonist. At least four types of opioid receptors have been identified in the central nervous system: mu, kappa, sigma, and delta. The affinity of a particular antagonist for each receptor may not be equal. However, antagonist compounds may act centrally or peripherally, at specific opiate receptors, through a non-specific analeptic mechanism, or through a neurotransmitter system. The full understanding of the complex affects of antagonists must await the elucidation of opioid physiology.
The prior art antagonist compound naloxone has gained widespread use in anesthesia for the purpose of antagonizing opioid induced respiratory depression and sedation, (Editorial, British Journal of Anesthesia, Vol. 57, No. 6, June 1985, pp 547-549). The use of naloxone in the presence of unwanted opioid effects has predominantly occurred in the immediate post operative period.
Recent information has supported the need for caution in the use of naloxone. This need for caution is based on reports of unwanted side effects of naloxone itself, including ventricular dysrhythmia, hypertension and pulmonary oedema following intravenous administration. Another disadvantage of naloxone as an antagonist is that naloxone tends to also reverse or antagonize the analgesic component of opioids.
There is therefore a need for a safe antagonist of opioid agonists which will selectively antagonize respiratory depression without the undesirable side effects of naloxone and which preferably does not antagonize the analgesia component of the opioid agonists.